Dibenzocycloalkylenylidene pyrrolidine derivatives



United States Patent O 3,454,595 DIBENZOCYCLOALKYLENYLIDENE PYRROLIDINEDERIVATIVES Yoshio Deguchi, Suita, Hiroshi Nojima, Yao, and NaomichiKato, Ikeda, Japan, assignors to Fujisawa Pharmaceutical Co., Ltd.,Higashiku, Osaka, Japan, a company of Japan No Drawing. Filed July 6,1966, Ser. No. 563,084 Claims priority, application Japan, July 8, 1965,40/41,144, 40/41,145; July 13, 1965, 40/ 32,412 Int. Cl. C07d 27/04;A61k 27/00 US. Cl. 260326.81 3 Claims ABSTRACT OF THE DISCLOSURE 3(10,11 dihydro H dibenzo[a,d]cycloheptene- S-ylidene) pyrrolidinecompounds or 3-(5,6,7,l2-tetra hydrodibenzo[a,d]cyclooctene 12 ylidene)pyrrolidine compounds which have in 2-position a lower alkyl substituent and which may contain in l-position lower alkyl or phenyl loweralkyl substituents, their non-toxic acid addition salts, and theirquaternary ammonium salts have a surprisingly high antidepressantactivity and thus are useful antidepressants and tranquilizers. Examplesof such compounds are 1,2-dimethyl-, 1,2-diethyl-, l-ethyl-Z- methyl-,l-methyl-2-ethyl-, or, respectively l-benzyl-Z- methyl 3 (10,11 dihydro5H dibenzo [a,d] cycloheptene-5-ylidene) pyrrolidines or thecorresponding 3- (5,6,7,l2 tetrahydro dibenzo [a,d] cyclooctene l2-ylidene) pyrrolidines which may contain in one or both benzene ringshalogen or lower alkyl, and their hydrochlorides.

Rae-m R4 wherein R and R are individually hydrogen, halogen or loweralkyl, R is lower alkyl, R; is hydrogen, lower alkyl or aralkyl, and nis an integer from 2 to 3.

As used herein the term lower is intended to mean groups containing oneto six carbon atoms.

In above Formula I, lower alkyl of R R R and R may be straight orbranched, and includes methyl, ethyl, propyl, iso-propyl, butyl,iso-butyl, pentyl and hexyl; halogen of R and R includes chlorine,bromine, iodine and fluorine; aralkyl of R includes benzyl, tolylmethyl,phenethyl and the like.

It is an object of this invention to provide novel and usefuldibenzocycloalkylenylidene pyrrolidine derivatives being of greattherapeutic valve.

It is also an object of this invention to provide processes forpreparing the same.

Further objects will appear hereinafter.

The compounds represented by the Formula I, their non-toxic acidaddition salts and quaternary ammonium salts are characterized bymanifold actions on the central and peripheral nervous systems such asanaesthetic, narcosis-potentiating, tranquilizing, antidepressant,hypotherice mic, antichloinergic or antihistaminic action, and areuseful particularly as antidepressants and tranquilizers.

The Compounds I of this invention may be prepared by reduction of thedibenzocycloalkylenylidene pyrroline derivatives of the Formula II:

wherein R is lower alkyl or aralkyl and X is an acid residue.

In the above Formula III, lower alkyl and aralkyl of R represent thesame members as explained before, and an acid residue includes halidesuch as chloride, bromide and iodide; sulfate (H505); mono lower alkylsulfate (lower alkyl --SO such as methyl sulfate, ethyl sulfate and thelike; arylsulfonate (aryl --SO such as benzenesulfonate,toluenesulfonate and the like; tartrate [HOOC-CH(OH)CH(OH)COO-], and thelike.

The starting compounds used in this invention are novel and may beprepared as follows: For example, 2-alkyl-3- 10,11 dihydro 5Hdibenzo[a,d]cycloheptene 5- ylidene)-l-pyrroline [n is 2 in the FormulaII] or its derivatives which have a substituent on one or both of thebenzene ring, are obtained by the reaction of 5-(3- halopropylidene)10,11 dihydro 5H dibenzo[a,d] cycloheptene or its correspondingderivatives [cf. J. Org. Chem. 27, 4134-4137 (1962)] with analkanonitrile[e.g. acetonitrile, propionitrile, butyronitrile or thelike] in the presence of a metal halide [c.g. stannic chloride, ammoniumchloride, zinc chloride, boron fluoride or the like]. 2 alkyl 3(5,6,7,12 tetrahydro dibenzo [a,d] cyclooctene-l2-ylidene)-l-pyrrolineor its derivatives in which n is 3 in the Formula H, are obtained bysubjecting 12 (3 halopropylidene) 5,6,7,12 tetrahydrodibenzo [a,d]cyclooctene compounds to the same procedure as described above.Furthermore, the resulting compounds are treated with an appropriateN-alkylating agent (III) (e.g. lower alkyl halide, aralkyl halide,monoor di-lower alkyl (or aralkyl) sulfate, lower alkyl -(or aralkyl)arylsulfonate, mono-lower alkyl tartrate or the like to yield thecorresponding quaternary ammonium salts.

The reduction step in this reaction may be carried out by using themethods which are generally employed for the reduction of an ammoniumsalt, e.g., the reduction methods using alkali metal boron hydride,alkaline earth metal boron hydride or alkali metal aluminum hydride, orusing a metal and an acid, or by catalytic reduction and so forth.

Examples of alkali metal or alkaline earth metal boron hydrides asmentioned herein are lithium, sodium or potassium boron hydride; orcalcium, magnesium or barium boron hydride. In the reduction using ametal and an acid, the metals are exemplified by iron, zinc, tin and thelike, and the acids are exemplified by an inorganic or organic acid suchas hydrochloric acid, sulfuric acid, acetic acid and the like. Examplesof the catalysts useful in the catalytic reduction method are platiniumoxide, palladium-carbon, Raney nickel and the like.

In using an alkali metal or alkaline earth metal boron hydride, thereduction is generally carried out in a solvent such as water, methanol,ethanol, tetrahydrofuran, dioxane or the like, at room temperature orunder heating. When using water as the solvent, it is highly desirableto use a small amount of a base such as sodium carbonate, sodiumhydrogen carbonate or the like in order to stabilize the reagent to beused. When another solvent is employed, it is also advantageous to carryout the reaction in the presence of a small amount of the base mentionedabove.

In using alkali metal aluminum hydride, the reduction may be carriedout, under substantially anhydrous conditions, in an inert solvent suchas methanol, diethyl ether, dibutyl ether, tetrahydrofuran, dioxane orthe like, at room temperature or under heating, according to theconventional method known in the art. Also, the reduction using a metaland an acid, and the catalytic reduction may be carried out inaccordance with conventional methods. The catalytic reduction may becarried out under pressure.

Thus Compounds I wherein R is hydrogen, may be converted to thecorresponding Compounds I wherein R is lower alkyl or aralkyl bytreating the former compounds with N-alkylating agents of Formula III inthe presence or absence of a base. Examples of N-alkylating agents arelower alkyl or aralkyl halides, monoor dilower alkyl (or aralkyl)sulfates, lower alkyl (or aralkyl) arylsulfonates, mono-lower alkyltartrate and the like. In this treatment, the Compounds I wherein R ishydrogen, may be employed either in the form of the free bases or in theform of the acid addition salts. When using the acid addition salts, thereaction may preferably be carried out in the presence of a base whichis advantageously used in an approximately equimolecular amount to theamount of acid addition salts to be reacted. In this case, if an excessamount of a base is employed, the quaternary ammonium saltscorresponding to the free bases and the N-alkylating agents to be used,may be produced. When using the free bases, the reaction may beadvantageously carried out in the absence of a base, or in the presenceof an approximately equimolecular amount of a base with an equimolecularor a slight excess amount of the N- alkylating agent.

As set forth above, lower alkyl halide is exemplified by methyl, ethyl,propyl, isopropyl, butyl, pentyl and hexyl chlorides, their bromides,their iodides and the like; aralkyl halide is exemplified by benzyl,tolyl and Compound 2-methyl-3-(10,11-dihydro-5H- dibenzo [a,d]cycloheptene- 5-ylldene) pyrrolidine hydroll-diliydrochloride.

1,2-dimethyl-3- 5H-dibenzo [a,d 5-ylidene) pyrrolidine hydrochloride.

c or e. 1-Methy1 2-ethyl-3-(10,11dihydro- 5H-dibenzo [a,d] cyclohepteneleycloheptenephenethyl chlorides, their bromides, their iodides and thelike; monoor di-lower alkyl sulfates and their aralkyl compounds areexemplified by methyl, ethyl, propyl, isopropyl, butyl, benzyl,tolylmethyl, phenethyl, dimethyl, diethyl sulfates and the like. Loweralkyl and aralkyl arylsulfonates are exemplified by methyl, ethyl,propyl, isopropyl, butyl, pentyl, benzyl tolylmethyl, phenethylbenzenesulfonates, their toluenesulfonates and the like. Mono-loweralkyl tartrate is exemplified by mono-methyl, mono-ethyl tartrate andthe like.

A few examples of the bases are sodium carbonate, potassium carbonate,sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide and thelike.

The N-alkylating reaction of the Compounds I wherein R is hydrogen, maybe carried out in lower aliphatic alcohol such as methyl or ethylalcohol, or in another inert organic solvent. And the reaction proceedsgenerally under heating and may proceed at a comparatively hightemperature and in closed vessel, although these conditions arenon-limitative.

The reaction with N-alkylating agents (III) as explained above, may besimilarly utilized for converting the Compounds I to the correspondingquaternary ammonium salts.

Also, thus obtained quaternary ammonium salts of the Compounds I may beconverted to the corresponding ammonium hydroxide compounds by treatingwith silver oxide or alkali metal hydroxide.

The Compounds I of this invention may be converted into a suitablenon-toxic acid addition salt. A suitable non-toxic acid is exemplifiedby an inorganic acid such as hydrochloric acid, hydrobromic acid,hydroiodic acid, nitric acid, phosphoric acid, sulfamic acid, sulfuricacid and the like, and an organic acid such as acetic acid, citric acid,tartaric acid, lactic acid, methanesulfonic acid, ethanesulfonic acidand the like.

The pharmacological studies carried out with a few representativecompounds of this invention gave the following results.

TABLE l.-TOXICITY LDsn (mg/kg. to mice) I.V. P.O

Compound TABLE 2 N arcosis-potentiatlng effect 1 Antihist-Antiacetylcholine efiect 1 potentiating dose -I e) Increase rates-ylidene) pyrrolidine hydroehlorlde l-Ethyl-2-rnethyl-3-(5,6,7,12-

tetrahydro-dibenzo [a,d] cyclooctene-lz-ylldene) pyrrolldtnehydrochloride.

1 The narcosis-potentiating eEect was determined on mice to which mg.'

Magnus method using the extracted small intestine of guinea-pigs.

The compounds of this invention can be administered orally andparenterally for therapeutical use. The pharmaceutically usefulcompositions containing the compounds of this invention together with asignificant amount of a non-toxic solid or liquid carrier are alsoincluded within a scope of this invention. Such compositions comprisesolid compositions such as tablets, pills, dispersi=ble powders andgranules, and liquid solutions such as injectable solutions, orallyadministrable solutions and suspensions.

In solid compositions one or more of the active compounds is or areadmixed with an inert diluent such as potato starch, lactose, calciumcarbonate and further additional substances, if needed, such as alubricant, e.g. magnesium stearate and the like; a binder, e.g. gelatinand the like; and a disintegrating agent, e.g. cellulose calciumglycolate and the like. Solid compositions also comprise capsules ofabsorbable material such as gelatin containing one or more activecompounds with or without the addition of diluents or excipients.

The following examples are given solely for the purpose of illustration.

Reference examples for preparing the starting compounds:

(1) 2-methyl-3-(10,1l-dihydro-SH-dibenzo [a,d]cycloheptene-S-ylidene)-1-pyrroline.A mixture of 2.6 g. of5-(3-bromopropylidene)-10,1l-dihydro-SH-dibenzo a,d!] cycloheptene (M.P.68-72/C.), 0.34 g. of acetonitrile, 5.2 g. of chlorobenzene and 2.1 g.of anhydrous stannic chloride was placed in a closed vessel and heatedat 130 C. for three hours. After completing the reaction, the reactionmixture was cooled, 20% aqueous sodium hydroxide solution was addedthereto and the mixture was heated whereafter the chlorobenzene layerwas separated. The remaining aqueous layer was extracted with ether. Themixture of the chlorobenzene layer and the ether extract solution wasextracted with 20% aqueous hydrochloric acid solution. The resultingaqueous layer was neutralized with 20% aqueous sodium hydroxide solutionand extracted with ether. The ether layer was dried over magnesiumsulfate and then ether was distilled off to yield 1.1 g. of2-methyl-3-(10,11-dihydro-5H-dibenzo [a,d]cycloheptene-S-ylidene)-1-pyrroline as a brown oil (B.P. 170-l75 C./0.15mm. Hg).

(2) 2-methyl-3-(5,6,7,12-tetrahydro-dibenzo [a,d]cyclooctene-l2-ylidene)-1-pyrroline.-A mixture of 1.9 g. oil2-(3-bromopropylidene)-5,6,7,12 tetrahydro dibenzo [a,d] cyclooctene(B.P. 175-l85 C./0.07 mm. Hg), 0.23 g. of acetonitrile, 3.7 g. ofchlorobenzene and 2.0 g. of stannic chloride was treated in the samemanner as described hereinabove under (1) to yield 0.2 g. of 2-methyl-3-(5,6,7,IZ-tetrahydro-dibenzo [a,d]cyclooctenel2-ylidene)-l-pyrroline as an oily substance.

Ultra-violet absorption spectrum:

rgggf 231.5 my, 6 18,100

max. (inflection) xZiZgP 244 m,., 6 13,840

6 Example 1 CH2) CH2) CH3 CH3 I -HC1 and its H01 salt2-methyl-3-(10,1l-dihydro-SH-dibenzo [a,d]cycloheptene-S-ylidene)-1-pyrroline hydrochloride ('B.'P. 170-175C./0.15 mm. Hg) (0.7 g.) was dissolved in 7 cc. of methanol. To thissolution, 0.17 g. of sodium boron hydride was added in small portionswhile stirring and cooling with ice and the mixture was kept for onehour to complete the reaction. The reaction mixture was acidified with10% aqueous hydrochloric acid solution, whereafter the methanol wasdistilled off. To the resulting residue there was added a 10% aqueoussodium hydroxide solution whereafter the separated oily substance wasextracted with ether. The ether layer, after drying over magnesiumsulfate, was distilled to yield 2-methyl-3- (l0,ll-dihydro-5H-dibenzo[a,d] cycloheptene-S-ylidene) pyrrolidine.

This substance was converted into its hydrochloride salt by adding ethercontaining hydrochloric acid to its solution in absolute ether underice-cooling. The resulting hydrochloride salt was recrystallized from amixture of absolute acetone and absolute ether to yield 0.38 g. ofcolorless crystals of the melting point 222-223 C.

Calculated for C H N-HClz C, 76.96; H, 7.10; N, 4.48. Found: C, 76.72;H, 7.01; N, 4.27.

Example 2 @fmt-Q glonig o o H II EES-Hm N (i) To a solution of 9.0 g. of2-ethyl-3-(10,11-dihydro- 5H dibenzo [a,d]cycloheptene-S-ylidene)-1-pyrroline (M.P. 93-98 C.) dissolved in cc. ofmethanol, there were added in small portions 2.5 g. of sodium boronhydride with stirring Within one hour and stirring of the solution wascontinued for two hours. The reaction mixture was acidified with 10%aqueous hydrochloride solution and the methanol was distilled off. Theresulting residue, after being alkalized with 20% aqueous sodiumhydroxide solution, was extracted with ether. The other layer was driedover magnesium sulfate and then the ether was distilled oil? to yield aslightly yellowish viscous oil. This oil was refined by distillation toyield 6.5 g. of 2-ethy1-3-(10,11-dihydro-5H-dibenzo [a,d] cycloheptene-5-ylidene) pyrrolidine (B.P. 174180- C./ 0.8 mm. Hg).

The substance (6.5 g.) obtained above was dissolved in 65 cc. ofabsolute ether. This solution was acidified with an ether solutionsaturated with gaseous hydrochloric acid under ice-cooling to yield2-ethyl-3-(10,11-dihydro- SI-I-dibenzo [a,d] cycloheptene-S-ylidene)pyrrolidine hydrochloride in the form of crystals, which were collectedby filtration, washed with ether and recrystallized from a mixture ofabsolute acetone and absolute ether to yield 5.8 g. of white crystals ofthe melting point 195187 C.

Calculated for C H NCl: C, 77.40; H, 7.42; N, 4.30; CI, 10.88. Found: C,77.60; H, 7.35; N, 4.08, Cl, 11.00.

(ii) To a solution of 0.7 g. of 2-ethyl-3-(10,11-dihydro-5H-dibenzo[a,d] cycloheptene-S-ylidene) pyrrolidine in 10 cc. of absolutemethanol, there were added 1.4 g. of ethyl iodide. This solution wasrefluxed in a waterbath for five hours. After completing the reaction,methanol was distilled off to yield a brown residue, which wascrystallized by the addition of ether. The resulting crystals werecollected by filtration and washed with ether to yield 1.0 g. of1,2-diethyl-3-(10,11-dihydro-5H-dibenzo [a,d] cycloheptene-S-ylidene)pyrrolidine hydroiodide. This substance was recrystallized from amixture of absolute acetone and absolute ether to yield crystals of themelting point 214-216 C.

Calculated for C H NI: C, 62.02; H, 6.34; N, 3.15; I, 28.49. Found: C,62.08; H, 6.21; N, 3.14; I, 28.77.

Example 3 tg o II II orn- I (i) CHa N CzH5N /6 CHI-m CzHs-N (i) To 3.8g. of 2-methyl-3-(10,1l-dihydro-SH-dibenzo [a,d]cycloheptene-S-ylidene)-1-pyrroline, there were added 8 g. of ethyliodide. This mixture was placed into -a closed vessel and heated at 80C. in a water-bath for one hour. After completing the reaction, thereaction mixture was cooled and the unreacted ethyl iodide was distilledolf to yield 5.5 g. of l-ethyl-2-methyl-3(10,1l-dihydro-SH-dibenzo [a,d]cycloheptene-S-ylidene)-1-pyrrolinium iodide in the form of yellowcrystals. These crystals were recrystallized from a mixture of acetoneand ether to yield yellow needles of the melting point 223 C.

Calculated for C H NI: C, 61.54; H, 5.63; N, 3.26. Found: C, 61.17; H,5.89; N, 3.20.

(ii) 1-ethyl-2-methyl-3-(10,11-dihydro 5H dibenzo [a,d]cycloheptene-S-ylidene)-1-pyrro1inium iodide (4.7 g.) was dissolved in 7cc. of methanol. To this solution there were added 1.4 g. of sodiumboron hydride within about 80 minutes with stirring and stirring of thesolution was continued for two hours to complete the reaction. Thereaction mixture was acidified with aqueous hydrochloric acid solutionand then the methanol was distilled off. The residual solution wasalkalized with aqueous sodium hydroxide solution and extracted withether. The ether layer was dried over magnesium sulfate and the etherwas distilled 01f. The resulting residue was further distilled underreduced pressure to yield 2.0 g. of 1-ethyl-2-methyl-3-(10,1l-dihydro 5Hdibenzo [a,d] cycloheptene-S-ylidene) pyrrolidine (B.P. 167 C./ 4 mm.Hg).

Ultra-violet absorption spectrum:

2.3 240 my, e 12,100

and its H01 salt Calculated for C H N: C, 87.08; H, 8.30; N, 4.61.Found: C, 87.41; H, 8.33; N, 4.76.

This substance was converted into its hydrochloride salt of the meltingpoint 250-253" C. according to the conventional method.

Calculated for C H NHCl: C, 77.96; H, 7.73; N, 4.13. Found: C, 77.95; H,7.79; N, 4.12.

(iii) 1-ethyl-2-rnethyl-3-(10,11-dihydro 5H dibrenzo [a,d]cycloheptene-S-ylidene) pyrrolidine (1.9 g.) arid 3.8 g. of ethyl iodidewere placed into a glass tube which was sealed, and heated at 6080 C.for one hour. After completing the reaction, the reaction mixture wascooled and unreacted ethyl iodide was distilled off to yield 2.8 g. of1,1-diethyl-2-methyl-3-(10,11-dihydro 5H dibenzo [a.d]cycloheptene-S-ylidene) pyrrolidinum iodide. This substance wasrecrystallized from a mixture of methanol and ether (M.P. 246 C. withdecomposition).

Ultra-violet absorption spectrum:

Calculated for C H NI: C, 62.74; H, 6.58; N, 3.04. Found: C, 62.81; H,6.53; N, 3.13.

Example 4 n) 0135- and its 1101 salt OHs-N--- (i) To 1.2 g. of2-ethyl-3-(l0,1l-dihydro-SH-dibenzo [a,d]cycloheptene-S-ylidene)-1-pyrroline there were added 5 cc. of methyliodide. This mixture was placed into a vessel which was closed, andheated at -80 C. in a water-bath for one hour. After completing thereaction, unreacted methyl iodide was distilled olf to yield 1.8 g. of1-methyl-2-ethyl-3-(10,1l-dihydro-5H-dibenzo [a,d]cycloheptene-S-ylidene)-1-pyrrolinium iodide in the form of yellowishbrown crystals of the melting point 224227 C.

(ii) l-methyl-2-ethyl-3-(10,11-dihydro 5H dibenzo [a,d]cycloheptene-S-ylidene)-1-pyrrolinium iodide (1.7 g.) was dissolved in20' cc. of methanol. To this solution there was gradually added 0.6 g.of sodium boron hydride with stirring and stirring of the solution wascontinued for one hour to complete the reaction. The reaction mixturewas acidified with an excess of 10% aqueous hydrochloric acid solution.Thereafter the methanol was distilled olf under reduced pressure. Theresidual solution was alkalized with 10% aqueous sodium hydroxidesolution and extracted with ether. The ether layer was dried overmagnesium sulfate and the ether was distilled off.

The residue was further distilled under reduced pressure to yield 0.7 g.of 1-methyl2-ethyl3-(10,1l-dihydro- SH-dibenzo [a,d]cycloheptene-S-ylidene) pyrrolidine in the form of a clear oilysubstance.

This substance was dissolved in 70 cc. of ether, there was added theretoether saturated with dried hydrochloric acid to yield its hydrochloridesalt in the form of white crystals. These crystals were separated byfiltration and recrystallized from a mixture of acetone and ether toyield 0.6 g. of white crystals of the melting point 210-213 C.

9 Calculated for C H N =HCl AH O: C, 76.39; H, 7.77; N, 4.05. Found: C,76.92; H, 7.70; N, 3.74.

Example 5 CH2)4 CHzla \C/ l H CH (i) W (ii) (CH2)3 CH1) \C/ \G/ II H CH3CH3 (111) d t m fi tll s alt a I C2H5N CzHrzHs (i) To 2.0 g. of2-methyl-3-(5,6,7,12-tetrahydro-dibenzo [a,d]cyclooctene-lZ-ylidene)-1-pyrroline (its hydrochloride has the meltingpoint 259261 C.), there were added 6.5 g. of ethyl iodide. This mixturewas placed into a vessel which was closed, and heated at 120 C. on anoil-bath for two hours. After completing the reaction, the reactionmixture was treated with the same manner as described in (i) of Example4 to yield crystals of 1-ethyl-2-methyl-3-(5,6,7,12 tetrahydro-dibenzo[a,d] cyclooctene-lZ-ylidene)-1-pyrrolinium iodide. These crystals wererecrystallized from ethanol to yield 2.5 g. of light yellow crystals ofthe melting point 309-310 C.

Ultra-violet absorption spectrum:

egg ,3 3,3 5 229 m 6 9,400

(ii) 1-ethyl-2-methyl-3-(5,6,7,1Z-tetrahydro-dibenzo [a, d]cyclooctene-12-ylidene)-l-pyrrolinium iodide (2.5 g.) was dissolved in25 cc. of methanol. To this solution there were added 0.9 g. of sodiumboron hydride taking about one hour with stirring. The reaction mixturewas treated in the same manner as described in (ii) of Example 4 toyield a brownish oily substance.

This substance was converted into its hydrochloride salt according tothe conventional method. The resulting salt was recrystallized from amixture of ethanol and ether to yield 1.5 g. of1-ethyl-2-methyl-3-(5,6,7,12-tetrahydro-dibenzo [a,d]cyclooctene-lZ-ylidene) pyrrolidine hydrochloride in the farm of faintbrown crystals of the melting point 262-263 C.

Ultra-violet absorption spectrum:

Calculated for C H N-HCl-H O: C, 76.53; H, 8.10; N, 3.88; Cl, 9.82.Found: C, 76.64; H, 8.19; N, 3.98; Cl, 10.01.

(iii) 1-ethyl-2-methyl-3 (5,6,7,12-tetrahydro-dibenzo [a,d]cyclooctene-lZ-ylidene) pyrrolidine (1.0 g.) and 3.2 g. of ethyl iodidewere placed into a glass tube which was sealed and heated at 120-130 C.in an oil-bath for two hours. After completing the reaction, thereaction mixture was cooled and unreacted ethyl iodide was distilled offto yield 1.1 g. of 1,1-diethyl-2-methyl-3-(5,6, 7,12-tetrahydro-dibenzo[a,d] cyclooctene-12-ylidene) pyrrolidinium iodide in the form of browncrystals. These crystals were purified by re-precipitation from amixture of acetone and ether [M.P. 128130 C. (dec.)].

Ultra-violet absorption spectrum:

Calculated for C H NL /2H O: C, 62.24; H, 7.03; N, 2.90; I, 26.30.Found: C, 62.12; H, 7.09; N, 2.87; I, 26.26.

Example 6 To 1.1 g. of 2-methyl-3-(3-methyl-l0,1l-dihydro-SH- dibenzo[a,d] cycloheptene-S-ylidene)-1-pyrroline there were added 7 cc. ofmethyl iodide. This mixture was placed into a vessel which was closedand heated at 7 080 C. in a water-bath for one hour. After completingthe reaction, unreacted methyl iodide was distilled 011 to yieldcrystals of 1,2-dimethyl-3-(3-methyl-10,1l-dihydro- SH-dibenzo [a,d]cycloheptene-S-ylidene)-1-pyrrolinium iodide. These crystals wererecrystallized from acetone to yield yellow needles of the melting point262 C.

Ultra-violet absorption spectrum:

xi gf 243 111,1, 6 6,492 271.5 m,., 6 5,770

Calculated for C H NI: C, 61.54; H, 5.63; N, 3.26. Found: C, 61.26; H,5.68; N, 3.12.

(ii) 1,2-dimethyl-3-(3-methyl-10,ll-dihydro-SH-dibenzo [a,d]cycloheptene-S-ylidene)-1-pyrrolinium iodide (1.7 g.) was dissolved in10 cc. of methanol. To this solution there was added 1.0 g. of sodiumboron hydride and the reaction mixture was treated in the same manner asdescribed in (ii) of Example 4 to yield 1,2-dimethyl-3-(3-methyl-10,1l-dihydro-SH-dibenzo [a,d] cycloheptene- 5-ylidene)pyrrolidine in the form of a faint yellowish viscous oil which showedone spot on a Kieselgel G. thin layer chromatograph (CHCl :C H OH=4:1).

This substance was converted into its hydrochloride salt according tothe conventional method. The resulting salt was recrystallized fromacetone to yield crystals of the melting point 260 C.

Nuclear magnetic resonance spectrum in CDCl 9.25 1(CH -CH=, doublet) 7.7q-(CH Ph, singlet) 7.6 1-(CH N=, singlet) 6.5-7.5 (=N-CH CH cn -cn -cz,multiplet) Ultra-violet absorption spectrum:

Calculated for C H NC1: C, 77.73; H, 7.71; N, 4.11. Found: C, 77.58; H,7.66; N, 4.37.

(iii) 1,2-dimethyl-3-(3 methyl-10,1l-dihydro-SH-dibenzo [a,d]cycloheptene-S-ylidene) pyrrolidine and 4.0 g. of methyl iodide wereplaced into a glass tube which was sealed and heated at 6080 C. for onehour. After completing the reaction, the reaction mixture was cooled andunreacted methyl iodide was distilled off to yield crystals of1,1,2-trimethyl-3-(3-methyl-10,1l-dihydro-SH- dibenzo [a,d]cycloheptene-S-ylidene) pyrrolidinium iodide. These crystals wererecrystallized from acetone and subsequently from a mixture of methanoland acetone to yield white crystals of the melting point 236-238 C.

Ultra-violet absorption spectrum:

Calculated for C H NI: C, 62.02; H, 6.33; N, 3.14. Found: C, 62.02; H,6.39; N. 2.99.

Example 7 (i) To 2.5 g. of 2-methyl-3-(3-chloro-10,1l-dihydro-SH-dibenzo [a,d] cycloheptane-S-ylidene)-1-pyrroline B.P. above 200C./0.2-0.3 mm. Hg), there were added 5.0 g. of ethyl iodide. Thismixture was heated at 60-80 C. on a water-bath. After completing thereaction, unreethyl 2 methyl-3-(3-chloro-10,1l-dihydro-SH-dibenzo [a,d]cycloheptene-S-ylidene) -1-pyrrolinium iodide. These crystals wererecrystallized from a mixture of methanol and acetone to yield 2.0 g. ofcrystals of the melting point 272-273 C.

Calculated for C H NICl: C, 56.97; H, 4.99; N, 3.01. Found: C, 57.13; H,4.90; N, 3.03.

(ii) 1 ethyl 2-methyl-3-(3-chloro-10,ll-dihydro-SH- dibenzo [a,d]cycloheptene-S-ylidene)-1-pyrrolinium iodide (2.1 g.) was dissolved in25 cc. of methanol. To this solution there was gradually added 1.0 g. ofsodium boron hydride within three hours, and the reaction mixture wastreated in the same manner as described in (ii) of Example 4 to yield1.6 g. of 1-ethyl-2-methyl-3-(3-chloro- 10,11-dihydro-5H-dibenzo [a,d]cyclohepene-S-ylidene) pyrrolidine in the form of an oily substance.

This oily substance was converted into its hydrochloride 1 saltaccording to the conventional method, The resulting salt wasrecrystallized from a mixture of methanol and acetone to yield crystalsof the melting point 257.5-- 259 C.

Ultra-violet absorption spectrum:

Example 8 CH2)2 I CHM" C \C/ [I H cum on;

ll i Br @l fi C II CH3? and its H01 salt Q C II CH3 (i)2-methyl-3-(10,11-dihydro-5H-dibenzo [a,d]cycloheptene-S-ylidene)-1-pyrroline was dissolved in cc. of methanol. Tothis solution there were added 4.7 g. of benzyl bromide, and thereaction mixture was heated at 90 C. in a water-bath for two and a halfhours. The solvent was distilled OE and the resulting residue was washedwith ether to yield a viscous oil of 2-methyl-3- (10,11dihydro-SH-dibenzo [a,d] cycloheptene-S-ylidene)-l-pyrrolinium bromide.

(ii) 2 methyl 3-(10,11-dihydro-5H-dibenzo [a,d]cycloheptene-S-ylidene)-1-pyrrolinium bromide (3.0 g.) was dissolved in30 cc. of methanol. To this solution there were added 2.0 g. of sodiumboron hydride within one hour, and the reaction mixture was treated inthe same manner as described in (ii) of Example 4 to yield 1 benzyl2-methyl3-(10,11-dihydro-5H-dibenzo [a,d] cycloheptene-S-ylidene)pyrrolidine in the form of a brown oil. This oil was distilled to yield1.4 g. of a yellow oil.

This substance was converted into its hydrochloride salt according tothe conventional method. This salt was recrystallized from a mixture ofmethanol and ether to yield white needles of the melting point 219 C.

(iii) 1 benzyl-2-methyl-3-(10,1l-dihydro-SH-dibenzo [a,d]cycloheptene-S-ylidene) pyrrolidine (0.4 g.) and 5.1 g. of methyl iodidewere placed into a glass tube which was sealed and treated in the samemanner as described in (iii) of the Example 7 to yield1-benzy1-1,2-dimethyl- 3 (10,11-dihydro-5H-dibenzo [a,d]cycloheptene-S-ylidene) pyrrolidinium iodide in the form of yellowcrystals. These crystals were recrystallized from a mixture of methanoland ether to yield white crystals of the melting point 200 C.

What we claim is:

1. A pyrrolidine compound selected from the group consisting of apyrrolidine compound of the formula R1 II m R4-N.

wherein R and R are members selected from the group consisting ofhydrogen, halogen, and lower alkyl, R is lower alkyl, R; is a memberselected from the group consisting of hydrogen, lower alkyl, and phenyllower alkyl, and n is an integer from 2 to 3, its non-toxic acidaddition salts, and its quaternary ammonium salts formed by reactionwith a quaternizing agent selected from the group consisting of loweralkyl halide, phenyl lower alkyl halide, monoor di-lower alkyl sulfate,monoor di-phenyl lower alkyl sulfate, monoor di-tolyl lower alkylsulfate, lower alkyl phenyl sulfonate, phenyl lower alkyl phenylsulfonate, lower alkyl tolyl sulfonate, phenyl lower alkyl tolylsulfonate, and mono-lower alkyl tartrate.

2. 1,2 dimethyl 3-(10,11-dihydro5H-dibenzo [a,d] cycloheptene-S-ylidene)pyrrolidine or its hydrochloride. 3.1-ethyl-2-methyl-3-(10,1l-dihydro-SH-dibenzo [a,d]cycloheptene-S-ylidene) pyrrolidine or its hydrochloride.

References Cited FOREIGN PATENTS 1,333,960 6/1963 France.

OTHER REFERENCES Noller, Chemistry of Organic Compounds, pp. 264, 6611965 ALEX MAZEL, Primary Examiner.

J. A. NARCAVAGE, Assistant Examiner.

U.S. Cl. X.R. 424-274

